Nicotinic acetylcholine receptors (nAChRs) belong to the superfamily of ligand-gated ion channels and are distributed widely in the human and nonhuman brain. At least 17 different subunits are currently known, which can coassemble in several ways resulting in 3 distinct types of nAChRs: (a) heteromeric receptors found in neuromuscular junctions, (b) heteromeric receptors found in the neurons, and (c) homomeric receptors also found in the neurons. These receptors mediate some effects of the endogenous neurotransmitter acetylcholine (ACh) and are also the biologic target of the tobacco alkaloid nicotine, which is known to mimic the actions of ACh at these receptors. Subunit compositions determine functional properties such as ion selectivity, conductance, channel open times, rate of desensitization, and sensitivity to certain neurotoxins.
Several nAChRs have been identified and characterized pharmacologically and have distinct patterns of distribution in the brain. For example, the nicotine α4β2 receptor subtypes are thought to play a role in various diseases, including various brain disorders (e.g., Alzheimer's disease), behavioral disorders (e.g., schizophrenia or substance abuse), various neoplasms (e.g., lung cancer), and other diseases (see e.g., J. Neurobiol. 2002; 53:633-640). It has been suggested that the loss of the α4β2 receptors may be an early presymptomatic marker for Alzheimer's disease (Prog Neurobiol. 2000; 61:75-111). These neuronal receptors may also be involved in the addiction to nicotine in chronic tobacco users, and tobacco use may increase the number of the α4β2 receptor sites (Annu Rev Pharmacol Toxicol. 1996; 36:597-613).
Therefore, and not surprisingly, the development of noninvasive imaging methods using PET and SPECT of the α4β2 receptor system has gained significant interest. For example, in previously known methods, PET studies have been performed with 11C-nicotine. However, the moderate affinity of nicotine for the α4β2 receptors resulted in relatively rapid clearance, and thus precluded its usefulness as a radiotracer. Based on the discovery of epibatidine binding to the α4β2 receptor (see e.g., Mol. Pharmacol. 1994; 45:563-569), various PET and SPECT radioligands have been developed (e.g., Behav Brain Res. 2000; 113:143-157), including various epibatidine analogs (e.g., WO 2005/000806) and pyridylether analogs that have been radiolabeled with 11C, 18F, 76Br, or 123I. Structures of these ligands are depicted in FIG. 1. Still other radioligands have been prepared in an effort to optimize in vivo imaging properties (see e.g., Bioorg Med. Chem. 2001; 9:3055-3058; J Nucl Med. 2004; 45:878-884; Bioorg Med. Chem. 2003; 11:5333-5343). However, toxicity issues and undesirable kinetic parameters have slowed the progression of these radiotracers for human studies. Nonetheless, human SPECT studies have now begun with 5-123I-A85380, and PET studies have begun with 2-18F-A85380 and, more recently, with 6-18F-A85380 (for structures, see FIG. 1).
Still further known α4β2 nAChR ligands include those described in EP 1 185 521, WO 2002/076434, and WO 2002/57275, with agonist activity, and various plant derived compounds (e.g., tetrahydroberberine, tetrahydropalmatine, stepholidine) with agonist and antagonist activity were described in WO 2004/069144. Other known agonist compounds include metanicotine compounds and azaadamantane-type compounds as presented in WO 2001/082978, and various substituted hexahydro-1H-pyrrolizines as discussed in U.S. Pat. No. 5,733,912.
It should be noted that almost all of the PET and SPECT radioligands developed thus far for the α4β2 nAChR subtype have been agonists, and only few selected α4β2 ligands with antagonistic activity were described in U.S. Pat. No. 5,691,365. Other known antagonists include lophotoxin, neosurugatoxin, and erysodine (J. Med. Chem. (1997) 40: 4169-4194). It has been suggested that α4β2 nAChRs may occur in 4 possible conformations: (a) a resting state, when no agonist is present; (b) an activated state, when an agonist is present and the ion channel is open; (c) a transiently desensitized state, when the ion channel is closed for small lengths of time (i.e., seconds); and (d) a desensitized state, when the ion channel is closed for longer periods of time. ACh is known to bind with different affinities to these different states (e.g., ACh has higher affinity for desensitized states). Remarkably, there are no published data that would indicate whether antagonists also would have different affinities for the various states, and/or whether their in vivo binding pattern would be different compared with that of the agonists such as 2-18F-A85380. Only recently, a derivative was prepared that included a 18F-radiolabel attached to the N-pyrrolidine ring ([18F]3-[1-(3-fluoropropyl)-(S)-pyrrolidin-2-ylmethoxy]-pyridine in: J. Label Compd Radiopharm. 2003; 46:1261-1268). While that compound revealed good in vitro affinity for the α4β2 receptor, no specific data were provided on the differential active states in the nicotinic ACh receptor. Moreover, in vivo studies failed to provide conclusive images or data that would co-localize the PET signals with known locations for the α4β2 receptor.
Therefore, while there are numerous radioligands for receptors of the α4β2 receptor type known in the art, all or almost all of them suffer from one or more disadvantages. Consequently, there is still a need to provide improved compositions and methods for radioligands for receptors of the α4β2 receptor type. Viewed from another perspective, there is also a need for selective positron emission tomography (PET) and single photon emission computed tomography (SPECT) radiotracers for animal and human diagnostic imaging studies.